DESCRIPTION (Applicant's abstract): Congestive heart failure (HF) is characterized by poor exercise tolerance, but the mechanisms of this exercise intolerance are poorly understood. During exercise, HF patients have exaggerated reflex increases in muscle sympathetic nerve activity (MSNA) and renal vasoconstriction (RCVR), both of which increase afterload, sodium and fluid retention, decrease cardiac output, and worsen congestive HF. Muscle mechanoreceptors, finely myelinated nerve endings in skeletal muscle which sense stretch, normally play a minor role in reflex responses to exercise, but in HF patients are the single most important mediators of the exaggerated reflex changes during exercise. The overall goal of this project is to understand the mechanisms underlying this enhanced muscle mechanoreceptor sensitivity in patients with HF. Evidence in animals suggests that muscle mechanoreceptors may be sensitized by ischemic metabolites generated during exercise. We hypothesize that in patients with HF, in whom exposure to ischemic metabolites is augmented, muscle mechanoreceptors are sensitized, leading to exaggerated increases in MSNA and RCVR during exercise. Aim 1: To determine if ischemic metabolites acutely sensitize muscle mechanoreflex control of MSNA and RCVR, and whether this sensitization is exaggerated in HF. Reflex changes in MSNA and RCVR will be measured in HF patients and normal controls before and after administration of pharmacological agents to block ischemic metabolite activation during rhythmic handgrip, which selectively activates the muscle mechanoreceptors. Aim 2: To determine if muscle mechanoreceptors are chronically sensitized to contraction in patients with HF. Very mild rhythmic handgrip, involuntary contractions, and external arm compression will be performed in HF patients and normal controls to determine if mechanoreceptors are chronically sensitized in HF patients even in the absence of ischemic metabolites. Aim 3: To determine if exercise conditioning reverses exaggerated muscle mechanoreflex control in humans with HF. After a 4 week conditioning program, which reverses the myopathy of HF, the above testing repeated to determine if the muscle mechanoreceptor sensitization is reversible.